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Elucidating the Degradation Pathways of Human Insulin in the Solid State

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Journal of Analysis and Testing 2024年第3期8卷 288-299页

作者： Andrew Fagan lorraine M.Bateman Joseph P.O'Shea Abina M.Crean SSPC the SFI Centre for Pharmaceutical Research School of Pharmacy University College Cork School of Pharmacy University College Cork Analytical and Biological Chemistry Research Facility (ABCRF) University College Cork School of Chemistry University College Cork

While there have been significant advances in the development of peptide oral dosage forms in recent years, highlighted by the clinical and commercial success of approved peptides such as Rybelsus?, there remain several barriers in the way of broad range applicability of this approach to peptide delivery. One such barrier includes the poor physical and chemical stability inherent to their structures, which persists in the solid state although degradation typically occurs at different rates and via different pathways in comparison to the solution state. Using insulin as a model peptide, this work sought to contribute to the development of analytical techniques for investigating common insulin degradation pathways. Chemically denatured,deamidated and aggregated samples were prepared and used to benchmark circular dichroism spectroscopy, reverse phase HPLC and size exclusion chromatography methods for the investigation of unfolding, chemical modifications and covalent aggregation of the insulin molecule respectively. Solid state degraded samples were prepared by heating insulin powder at 60 °C and 75% relative humidity for 1, 3, 5 and 7 d, and the degradation profiles of the samples were evaluated and compared with those observed in solution. While no unfolding was observed to occur, significant deamidation and covalent aggregation were detected. Reductive disulfide bond cleavage using dithiothreitol allowed for separation of the insulin A-and B-chains,offering a facile yet novel means of assessing the mechanisms of deamidation and covalent aggregation occurring in the solid state.

关键词： Biopharmaceutical analysis Covalent aggregation Deamidation Disulfide cleavage Insulin Solid state Stability

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Who Am I?

城市漫步（GBA版） 2024年第2期 34-35页

作者： lorraine Lee 不详

Beyond Shame is a mission-driven column,aimed at destigmatizing difficult human experiences,offering insights and strategies to empower personal growth,healing,and deeper connections.

关键词： healing offering insight

Beyond Shame:Reconciling Complex Parental Relationships When You Don't Know Where to Start,Begin with the End in Mind

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城市漫步（GBA版） 2024年第1期 52-53页

作者： lorraine Lee 不详

Beyond Shame is a missiondriven column,aimed at destigmatizing difficult human experiences,offering insights and strategies to empower personal growth,healing,and deeper connections.

关键词： offering insight Beyond

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摄影拥抱这个世界的悲欢离合

数码摄影 2024年第8期 69-79+68页

作者： lorraine Turci 金向怡

从19世纪初期到现在，摄影逐渐从记录性的工具演变成为一种文化，而作为一种文化，探索和实验是其发展的重要手段。从探索与实验的角度出发，我们一直都在坚持与年轻摄影师群体的合作——“锐像”便是一个专门介绍中、外年轻摄影师的栏... 详细信息

从19世纪初期到现在，摄影逐渐从记录性的工具演变成为一种文化，而作为一种文化，探索和实验是其发展的重要手段。从探索与实验的角度出发，我们一直都在坚持与年轻摄影师群体的合作——“锐像”便是一个专门介绍中、外年轻摄影师的栏目。《数码摄影》杂志通过对他们的深入采访，将他们和他们最具实验性、探索性的作品介绍给广大的读者群体。面对这些年轻人的“新锐”作品，也许很多人没有办法能够立刻接受，但是我们要以一种发展的“眼光”来看待事物的发展，好与坏、对与错并不是由简单地肯定或否定来盖棺定论，因为这是一个过程，一个事物发展的过程。本期的“锐像”栏目，向大家介绍的是法国青年摄影师lorraine Turci，她将人作为自己作品的中心，以独特的视角讲述了领土、身份、传承、演变和保护之间的复杂关系——在她的叙事中，世界的多元性呈现出一种动荡之美。

关键词： lorraine Turci 航海作者摄影旅行采访

An efficient approach for anti-jamming in IRNSS receivers using improved PSO based parametric wavelet packet thresholding

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Satellite Navigation 2022年第3期3卷 51-70,I0003页

作者： Jacob Silva lorraine Kambham Madhu Ramarakula Department of ECE University College of EngineeringJNTUKKakinadaAndhra Pradesh533003India

The Indian Regional Navigation Satellite System provides accurate positioning service to the users within and around India,extending up to 1500 ***,when a receiver encounters a Continuous Wave Interference,its positioning accuracy degrades,or sometimes it even fails to *** Packet Transform(WPT)is the most widely used technique for anti-jamming in Global Navigation Satellite System *** the conventional method suffers from threshold drifting and employs inflexible thresholding ***,to address these issues,an efficient approach using Improved Particle Swarm Optimization based Parametric Wavelet Packet Thresholding(IPSO-PWPT)is ***,a new parameter adaptive thresholding function is ***,a new form of inertia weight is presented to enhance the performance of ***,IPSO is used to optimize the key parameters of ***,the implementation of the IPSO-PWPT anti-jamming algorithm is *** performance of the proposed technique is evaluated for various performance metrics in four jamming *** evaluation results manifest the proposed method’s efficacy compared to the conventional WPT in terms of anti-jamming ***,the results show the ability of the new thresholding function to process various signals ***,the findings reveal that the improved PSO outperforms the variants of PSO.

关键词： Continuous wave interference(CWI) IRNSS Particle swarm optimization(PSO) Wavelet packet transform(WPT)

Extracellular vesicles as a potential therapeutic for age-related macular degeneration

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Neural Regeneration Research 2023年第9期18卷 1876-1880页

作者： lorraine L.C.Chow Ben Mead School of Optometry and Vision Sciences Cardiff UniversityCardiffUK

Age-related macular degeneration is a major global cause of central visual impairment and seve re vision *** an aging population,the already immense economic burden of costly anti-vascular endothelial growth fa ctor treatment is likely to *** addition,current conventional treatment is only available for the late neovascular stage of age-related macular degeneration,and injections can come with potentially devastating complications,introducing the need for more economical and ris kfree *** recent years,exosomes,which are nano-sized extracellular vesicles of an endocytic origin,have shown immense potential as diagnostic biomarkers and in the therapeutic application,as they are bestowed with characte ristics including an expansive cargo that closely resembles their parent cell and exceptional ability of intercellular communication and targeting neighboring *** are currently undergoing clinical trials for various conditions such as type 1 diabetes and autoimmune diseases;however,exosomes as a potential therapy for seve ral retinal diseases have just begun to undergo scrutinizing investigation with little literature on age-related macular degeneration *** article will focus on the limited literature availa ble on exosome transplantation treatment in age-related macular degeneration animal models and in vitro cell cultures,as well as briefly identify future research *** literature on exosome therapy using agerelated macular degeneration rodent models includes laser retinal injury,N-methyl-N-nitrosourea,and royal college of surgeon models,which mimic inflammatory and degenerative aspects of agerelated macular *** have shown promising results in preserving retinal function and morphology,as well as protecting photoreceptors from *** from their respective cellular origins may also act by regulating the expression of various inflammatory cyto kines,mRNAs,and proteins involved in photo

关键词： age-related macular degeneration exosomes extracellular vesicles miRNA neuroprotection photoreceptors retina retinal pigment epithelium

Downscaling future climate scenarios to fine scales for hydrologic and ecological modeling and analysis

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Ecological Processes 2012年第1期1卷 109-123页

作者： lorraine E Flint Alan L Flint U.S.Geological Survey Placer Hall6000 J St.SacramentoCA 95819USA

Introduction:Evaluating the environmental impacts of climate change on water resources and biological components of the landscape is an integral part of hydrologic and ecological investigations,and the resultant land and resource management in the twenty-first *** of both climate and simulated hydrologic parameters on ecological processes are relevant at scales that reflect the heterogeneity and complexity of *** present,simulations of climate change available from global climate models[GCMs]require downscaling for hydrologic or ecological ***:Using statistically downscaled future climate projections developed using constructed analogues,a methodology was developed to further downscale the projections spatially using a gradient-inverse-distancesquared approach for application to hydrologic modeling at 270-m spatial ***:This paper illustrates a methodology to downscale and bias-correct national GCMs to subkilometer scales that are applicable to fine-scale environmental *** scenarios were chosen to bracket the range of future emissions put forth by the Intergovernmental Panel on Climate ***-scale applications of downscaled datasets of ecological and hydrologic correlations to variation in climate are ***:The methodology,which includes a sequence of rigorous analyses and calculations,is intended to reduce the addition of uncertainty to the climate data as a result of the downscaling while providing the fine-scale climate information necessary for ecological *** results in new but consistent data sets for the US at 4 km,the southwest US at 270 m,and California at 90 m and illustrates the utility of fine-scale downscaling to analyses of ecological processes influenced by topographic complexity.

关键词： downscaling climate change spatial scale scenarios

Fine-scale hydrologic modeling for regional landscape applications:the California Basin Characterization Model development and performance

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Ecological Processes 2013年第1期2卷 254-274页

作者： lorraine E Flint Alan L Flint James H Thorne Ryan Boynton Water Resources Discipline U.S.Geological SurveyPlacer Hall6000 J StreetSacramentoCA 95819-6129USA Information Center for the Environment University of CaliforniaDavisCA95616USA

Introduction:Resource managers need spatially explicit models of hydrologic response to changes in key climatic drivers across variable landscape *** demonstrate the utility of a Basin Characterization Model for California(CA-BCM)to integrate high-resolution data on physical watershed characteristics with historical or projected climate data to predict watershed-specific hydrologic ***:The CA-BCM applies a monthly regional water-balance model to simulate hydrologic responses to climate at the spatial resolution of a 270-m *** model has been calibrated using a total of 159 relatively unimpaired watersheds for the California ***:As a result of calibration,predicted basin discharge closely matches measured data for validation *** CA-BCM recharge and runoff estimates,combined with estimates of snowpack and timing of snowmelt,provide a basis for assessing variations in water *** important output variable,climatic water deficit,integrates the combined effects of temperature and rainfall on site-specific soil moisture,a factor that plants may respond to more directly than air temperature and precipitation *** outputs are calculated for each grid cell,allowing results to be summarized for a variety of planning units including hillslopes,watersheds,ecoregions,or political ***:The ability to confidently calculate hydrologic outputs at fine spatial scales provides a new suite of hydrologic predictor variables that can be used for a variety of purposes,such as projections of changes in water availability,environmental demand,or distribution of plants and *** we present the framework of the CA-BCM model for the California hydrologic region,a test of model performance on 159 watersheds,summary results for the region for the 1981–2010 time period,and changes since the 1951–1980 time period.

关键词： Water balance Basin models Watershed hydrology Climate change Downscaling Basin characterization model

Oxidative stress-induced mitochondrial dysfunction in a normal colon epithelial cell line

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World Journal of Gastroenterology 2017年第19期23卷 3427-3439页

作者： Nandakumar Packiriswamy Kari F Coulson Susan J Holcombe lorraine M Sordillo Department of Large Animal Clinical Sciences College of Veterinary Medicine Michigan State University

AIM To determine how a normal human colon cell line reacts to microbial challenge as a way to study oxidative stress-induced responses associated with inflammatory bowel *** Normal human colon epithelial cells(ATCC?CRL.1790?)were stimulated with either heat killed *** or heat killed murine cecal contents(HKC)and examined for several relevant biomarkers associated with inflammation and oxidative stress including cytokine production,mitochondrial autophagy and oxidant ***α,IL-1βand IL-8 protein concentrations were measured within the *** microscopy was performed to quantify the production of reactive oxygen species(ROS)using an oxidation responsive fluorogenic *** morphology and mitochondrial membrane potential was assessed by dual staining using COXIV antibody and a dye concentrating in active *** ROS scavenger was used to determine the source of ROS in stimulated *** was detected by staining for the presence of autophagic *** controls for autophagy and ROS/RNS experiments were treated with rapamycin and *** morphology,ROS production and autophagy microscopy experiments were analyzed using a custom acquisition and analysis microscopy software(Image J).RESULTS Exposing CRL.1790 cells to microbial challenge stimulated cells to produce several relevant biomarkers associated with inflammation and oxidative *** killed cecal contents treatment induced a 10-12fold increase in IL-8 production by CRL.1790 cells compared to unstimulated controls at 6 and 12 h(P<0.001).Heat killed *** stimulation resulted in a4-5 fold increase in IL-8 compared to the unstimulated control cells at each time point(P<0.001).Both heat killed *** and HKC stimulated robust ROS production at 6(P<0.001),and 12 h(P<0.01).Mitochondrial morphologic abnormalities were detected at 6 and12 h based on reduced mitochondrial circularity and decreased mitochondrial membr

关键词： Colon cancer cell line CRL.1790 cells Inflammation Mitochondria Microbial stimulation Interleukin-8 Autophagy